Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
Sci Immunol. 2023 Aug 18;8(86):eadg3517. doi: 10.1126/sciimmunol.adg3517. Epub 2023 Aug 11.
The skin needs to balance tolerance of colonizing microflora with rapid detection of potential pathogens. Flexible response mechanisms would seem most suitable to accommodate the dynamic challenges of effective antimicrobial defense and restoration of tissue homeostasis. Here, we dissected macrophage-intrinsic mechanisms and microenvironmental cues that tune macrophage signaling in localized skin infection with the colonizing and opportunistic pathogen Early in skin infection, the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by γδ T cells and hypoxic conditions within the dermal microenvironment diverted macrophages away from a homeostatic M-CSF- and hypoxia-inducible factor 1α (HIF-1α)-dependent program. This allowed macrophages to be metabolically rewired for maximal inflammatory activity, which requires expression of and generation of itaconate, but not HIF-1α. This multifactorial macrophage rewiring program was required for both the timely clearance of bacteria and for the provision of local immune memory. These findings indicate that immunometabolic conditioning allows dermal macrophages to cycle between antimicrobial activity and protection against secondary infections.
皮肤需要在耐受定植微生物群的同时，快速检测潜在病原体。灵活的反应机制似乎最适合适应有效的抗菌防御和组织内稳态恢复的动态挑战。在这里，我们剖析了内在的巨噬细胞机制和微环境线索，这些机制和线索可以调节定植和机会性病原体局部皮肤感染中的巨噬细胞信号。在皮肤感染早期，γδ T 细胞产生的细胞因子粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 和真皮微环境中的缺氧条件使巨噬细胞偏离由 M-CSF 和缺氧诱导因子 1α (HIF-1α) 依赖的程序的稳态。这使得巨噬细胞能够进行代谢重编程以实现最大的炎症活性，这需要表达 和生成衣康酸，但不需要 HIF-1α。这种多因素的巨噬细胞重编程程序对于及时清除细菌和提供局部免疫记忆都是必需的。这些发现表明，免疫代谢调节使真皮巨噬细胞能够在抗菌活性和预防二次感染之间循环。
